University of Minnesota Clinical Center for the Study of Acute Pancreatitis and Diabetes

明尼苏达大学急性胰腺炎和糖尿病临床研究中心

基本信息

批准号：
10458669
负责人：
Melena D. Bellin
金额：
$ 27.13万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458669
关键词：
Abate Accident and Emergency department Acinar Cell Address Adult Affect American Antibodies Antigens Autoantibodies Autoimmunity B-Lymphocytes Beta Cell Bioinformatics Biological Markers CD8-Positive T-Lymphocytes Cell Death Cell physiology Cells Cellular Stress Cessation of life Childhood Clinics and Hospitals Data Defect Development Diabetes Mellitus Diabetes autoantibodies Diagnosis Disease Endocrine Enrollment Environmental Exposure Epidemiology Event Exhibits Exocrine pancreas Frequencies Functional disorder Genetic Markers Glucose Goals Health Hospitalization Hyperglycemia Immune Immunologics Immunology Individual Inflammation Injury Insulin Resistance Insulin deficiency Insulin-Dependent Diabetes Mellitus International Intravenous Longitudinal Studies Longitudinal cohort Longitudinal observational study Measures Metabolic Metabolic dysfunction Minnesota Oral Oxidative Stress Pancreas Pancreatic Injury Pancreatitis Participant Patient Recruitments Patients Peripheral Blood Mononuclear Cell Persons Phenotype Post-Translational Protein Processing Prevalence Recording of previous events Recurrence Research Personnel Risk Risk Factors Role Sampling Self Tolerance Serum Signal Transduction Stimulus T-Lymphocyte Testing Tissues Universities Work acute pancreatitis autoimmune pathogenesis autoreactive T cell biobank chronic pancreatitis clinical center clinical risk cohort cytokine diabetes risk experience gastrointestinal high risk human leukocyte antigen testing improved inflammatory milieu injured insulin secretion insulin sensitivity intravenous glucose tolerance test islet macrophage medical specialties multimodality neoantigens neutrophil patient subsets prevent recruit response tissue injury

项目摘要

Abstract Patients with a history of acute pancreatitis (AP) are at high risk for developing diabetes mellitus (DM), affecting about 1 in 4 patients after AP. Clinical risk factors are poorly understood, and mechanisms leading to development of DM after AP are unknown. We propose to study risk for and mechanisms underlying development of DM after AP; specifically we will study the contributions of beta cell autoimmunity, defects in insulin secretion, and insulin resistance to DM after AP. In type 1 diabetes mellitus (T1DM) insulin deficiency results from targeted autoimmune destruction of the islet β-cells; this autoimmunity is triggered by unknown environmental exposures in genetically susceptible individuals. We hypothesize that tissue injury combined with an altered inflammatory milieu during AP activates β-cell autoimmunity (T1DM) in a subset of patients with AP-related DM. Our preliminary data collectively suggests an increased signal of β-cell autoimmunity in patients with recurrent AP or chronic pancreatitis and DM. We hypothesize that patients who develop DM after AP will have reduced insulin secretion (due to pancreatic injury), reduced insulin sensitivity, and a subset will have β-cell autoimmunity. Our overall goal is to establish a carefully phenotyped multi-center longitudinal cohort of adults diagnosed with AP to determine clinical risk factors for DM, define metabolic dysfunction in AP-DM, and determine the immunologic contributions to AP-DM. The University of Minnesota-Clinical Center investigators are leaders in the fields of AP, DM, and T1DM immunology and are ideally suited to address the consortium objectives. In Aim 1, we will identify, recruit, and enroll adults (N=1250) consortium-wide at 0 to 3 months after a first episode of acute pancreatitis for a longitudinal study to advance our understanding of progression to DM after AP. We will determine clinical risk factors for DM after AP. In Aim 2, we will define mechanistic mechanisms of AP-related DM by studying 250 patients after AP (from Aim 1) with mixed meal tolerance and frequent sample intravenous glucose tolerance tests to measure insulin secretion and insulin sensitivity. In Aim 3, we will define immunologic mechanisms of disease by determining the contribution of β-cell autoimmunity in development of DM after AP. We will perform HLA-typing and β-cell autoantibodies in the entire cohort from Aim 1 and assess cellular autoimmunity with T-cell and B-cell tetramers in a subset of 60 subjects selected by DM and AAb status. A separate tissue biobank will be used to evaluate islet infiltrates in recurrent AP. This work will contribute significantly to both our understanding of pancreatogenic DM and T1DM. In the setting of AP, better defining the pathophysiologic mechanisms of disease is critical to improving treatment and delaying or preventing progression to DM. For T1DM, this work provides an avenue to better identify an important role for islet β-cells as a key trigger for the self-reactive immune cells causing autoimmunity.

抽象的患有急性胰腺炎病史（AP）的患者患糖尿病（DM）的高风险 AP后影响大约4个患者中的1例。临床危险因素的理解很少，以及导致的机制 AP后DM的开发未知。我们建议研究基本机制的风险和机制 AP之后的DM开发；具体而言，我们将研究β细胞自动免疫的贡献，缺陷 AP后，胰岛素分泌和对DM的胰岛素抵抗。在1型糖尿病（T1DM）胰岛素缺乏症中，胰岛的自身免疫性破坏引起 β细胞；这种自身免疫是由遗传易感性的未知环境暴露触发的个人。我们假设组织损伤与AP期间的炎症环境相结合与AP相关的DM患者子集中的β细胞自身免疫（T1DM）。我们的初步数据集体表明复发性AP或慢性胰腺炎和 DM。我们假设AP后发展DM的患者将减少胰岛素分泌（由于胰腺损伤），胰岛素敏感性降低，子集将具有β细胞自身免疫性。我们的总体目标是建立一个经过精心表现的多中心纵向队列的成年人。 AP确定DM的临床风险因素，定义AP-DM中的代谢功能障碍，并确定对AP-DM的免疫学贡献。明尼苏达大学临床中心的调查人员是 AP，DM和T1DM免疫学领域非常适合解决财团目标。在 AIM 1，我们将在第一次后0到3个月确定，招募和招募成年人（n = 1250）联盟急性胰腺炎的发作，用于一项纵向研究，以提高我们对DM进展的理解 AP。我们将确定AP后DM的临床风险因素。在AIM 2中，我们将定义与AP相关的DM通过研究AP后的250名患者（来自AIM 1），并经常样品静脉注射葡萄糖耐受性测试，以测量胰岛素分泌和胰岛素敏感性。在AIM 3中，我们将通过确定β细胞自身免疫性的贡献来定义疾病的免疫机制 AP后DM的开发。我们将在整个队列中执行HLA型和β细胞自身抗体 AIM 1并用T细胞和B细胞四聚体评估细胞自身免疫性，其中60个受试者的子集 DM和AAB状态。单独的组织生物库将用于评估复发性AP中的胰岛浸润。这项工作将有助于我们对胰腺生成DM和T1DM的理解。在设置中在AP中，更好地定义疾病的病理生理机制对于改善治疗和延迟或防止发展为DM。对于T1DM，这项工作为更好地识别胰岛细胞的重要作用是引起自身免疫性的自反应性免疫球的关键触发因素。